Pneumocystis carinii pneumonia (PcP) continues to be a significant cause of morbidity and mortality among patients with AIDS, cancer, transplant recipients, or other immunocompromising illnesses. Despite the many advances in medical practice and the availability of effective anti-P. carinii antibiotics, the morbidity and mortality due to P. carinii pneumonia has changed little in the last 20 years and remains unacceptably high. Overall, mortality is about 10%/episode in AIDS patients and even higher, up to 40%/episode, in non- AIDS patients. This is likely related to the fact that effective antibiotic-mediated killing of Pc does not immediately reduce the severe immunopathological component of PcP that is driven by the concurrent presence of T cells and Pc antigen in the lung. We have established, over the past 9 years, the role of the Pc-specific immune-mediated inflammatory response in the immunopathogenesis of lung injury associated with PcP. Specifically, we have demonstrated a critical role for CD8+ T cells in the initiation of this inflammatory response in the CD4+ T cell depleted host. Our working hypothesis is that the host's T cell-mediated immune response to infection by P. carinii is a major contributor to the morbidity and mortality of PcP, and that understanding how this injury progresses is absolutely critical to the effective control of this response and improving patient outcomes. In addition to targeting T cells, we have identified specific inflammatory events downstream of T cell activation that may have roles in the generation and persistence of PcP-related inflammatory lung injury. These events include the activation of alveolar macrophages (AMs), the production of TNF-1, and enhanced cell signaling through NF-kB and MAPK. Our goal is to further characterize the cellular and molecular events leading to lung injury during PcP for the purpose of identifying specific pathways or combinations of pathways that lend themselves to therapeutic intervention. "Proof of principle" and candidate pathways have been identified during our initial studies. We are optimistic that the experiments outlined herein will lead to translational clinical trials as emphasized in the NIH roadmap. PUBLIC HEALTH RELEVANCE The morbidity and mortality due to P. carinii pneumonia has changed little in the last 20 years and remains unacceptably high. Overall, mortality is about 10%/episode in AIDS patients and even higher, up to 40%/episode, in non-AIDS patients. The experiments outlined in this proposal are designed to lead to a translational clinical trial designed to improve the management of patients with P. carinii pneumonia.